Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson's disease: A comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. OBJECTIVE: To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. METHODS: We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). RESULTS: All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). CONCLUSION: Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.

Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Proinflammatory profile in the skin of Parkinson's disease patients with and without pain.

BACKGROUND: Pain is a common non-motor symptom of Parkinson`s disease (PD), however, its pathomechanism remains elusive. OBJECTIVE: We aimed to investigate the local gene expression of selected proinflammatory mediators in patients with PD and correlated our data with patients`pain phenotype. METHODS: We recruited 30 patients with PD and 30 healthy controls. Pain intensity of patients was assessed using the Numeric Rating Scale (NRS) and patients were stratified into PD pain (NRS≥4) and PD No Pain (NRS<4) subgroups. Skin punch biopsies were immunoassayed for protein-gene product 9.5 as a pan-neuronal marker and intraepidermal nerve fiber density (IEFND). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to assess the gene expression of inflammatory mediators in the skin compared to controls. RESULTS: Patients with PD had lower distal IENFD compared to healthy controls. In skin samples, IL-2 (p<0.001) and TNF-α (p<0.01) were expressed higher in PD patients compared to controls. IL-1ß (p<0.05) was expressed higher in the PD pain group compared to healthy controls. PD patients with pain receiving analgesics had a lower expression of TNF-α (p<0.05) in the skin compared to those not receiving treatment. CONCLUSIONS: Our data suggest the occurrence of a local, peripheral inflammatory response in the skin in PD, but do not support this being a relevant factor contributing to pain in PD.

Troubleshooting Gait Disturbances in Parkinson's Disease With Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson's disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management.

Extrahepatic portosystemic shunts as an unusual but treatable cause of hyperammonemic encephalopathy in a noncirrhotic patient - a case report.

We report a case of hyperammonemic encephalopathy due to extrahepatic portosystemic shunts in a noncirrhotic patient. A 79-year-old woman suffered from episodic confusion, disorientation, dysphasia and fluctuating level of consciousness. Electroencephalography (EEG) showed encephalopathic changes and serum levels of ammonia were elevated. Further investigation revealed mesenterorenal and mesenterocaval shunts, which had possibly evolved after pancreatic surgery 5 years ago. After shunt obliteration, the symptoms completely resolved, ammonia levels dropped to the normal range and EEG findings normalized. Clinicians should be aware of this rare but treatable cause of encephalopathy in noncirrhotic patients.

Deep Brain Stimulation for Arm Tremor: A Randomized Trial Comparing Two Targets.

OBJECTIVE: Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) effectively suppresses arm tremor. Uncontrolled studies suggest the posterior subthalamic area (PSA) may be superior. We compared the intra-individual efficacy of VIM- versus PSA-DBS on tremor suppression and arm function. METHODS: We performed a randomized, double-blind, crossover trial at Oslo University Hospital in patients (18-80 years) with isolated or combined action tremor affecting at least one arm. Four-contact DBS leads were implanted (bi- or unilaterally) with a trajectory to cover the VIM (upper two contacts) and PSA (lower two contacts). Patients were randomized (1:1 ratio) post-surgery to: Group 1, VIM-stimulation months 0-3 (period 1), then PSA-stimulation months 4-6 (period 2); Group 2, PSA-stimulation first, then VIM-stimulation. Primary endpoint was the difference in improvement from baseline to the end of the VIM- versus PSA-period in the sum of the dominant arm tremor scores of the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS), items 5/6 + 10-14. RESULTS: Forty-five patients were randomized to Group 1 (n = 23) or 2 (n = 22). In the primary endpoint per-protocol analysis (mixed model, n = 40), mean difference in the sum FTMTRS score improvement for the dominant arm was -2.65 points (95% CI -4.33 to -0.97; p = 0.002). The difference in favour of PSA stimulation was highly significant in period 2, but not period 1. INTERPRETATION: Our randomized trial demonstrated that PSA stimulation provided superior tremor suppression compared with VIM stimulation. A period effect reducing tremor for up to three months in both groups was most likely attributed to a post-surgery stun effect. ANN NEUROL 2022;91:585-601.

Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice.

BACKGROUND: Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. METHODS: We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)-/- mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4+/CD8-, CD4-/CD8+, or CD4+/CD8+ (JHD-/-) mice into the RAG-1-/- mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. RESULTS: AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68-78) and surrounding the pathogenically relevant S129 (120-134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. CONCLUSIONS: Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.

Double-blind cross-over pilot trial protocol to evaluate the safety and preliminary efficacy of long-term adaptive deep brain stimulation in patients with Parkinson's disease.

INTRODUCTION: After several years of brain-sensing technology development and proof-of-concept studies, adaptive deep brain stimulation (aDBS) is ready to better treat Parkinson's disease (PD) using aDBS-capable implantable pulse generators (IPGs). New aDBS devices are capable of continuous sensing of neuronal activity from the subthalamic nucleus (STN) and contemporaneous stimulation automatically adapted to match the patient's clinical state estimated from the analysis of STN activity using proprietary algorithms. Specific studies are necessary to assess superiority of aDBS vs conventional DBS (cDBS) therapy. This protocol describes an original innovative multicentre international study aimed to assess safety and efficacy of aDBS vs cDBS using a new generation of DBS IPG in PD (AlphaDBS system by Newronika SpA, Milan, Italy). METHODS: The study involves six investigational sites (in Italy, Poland and The Netherlands). The primary objective will be to evaluate the safety and tolerability of the AlphaDBS System, when used in cDBS and aDBS mode. Secondary objective will be to evaluate the potential efficacy of aDBS. After eligibility screening, 15 patients with PD already implanted with DBS systems and in need of battery replacement will be randomised to enter a two-phase protocol, including a 'short-term follow-up' (2 days experimental sessions during hospitalisation, 1 day per each mode) and a 'long-term follow-up' (1 month at home, 15 days per each mode). ETHICS AND DISSEMINATION: The trial was approved as premarket study by the Italian, Polish, and Dutch Competent Authorities: Bioethics Committee at National Oncology Institute of Maria Sklodowska-Curie-National Research Institute in Warsaw; Comitato Etico Milano Area 2; Comitato Etico IRCCS Istituto Neurologico C. Besta; Comitato Etico interaziendale AOUC Città della Salute e della Scienza-AO Ordine Mauriziano di Torino-ASL Città di Torino; De Medisch Ethisch Toetsingscommissie van Maastricht UMC. The study started enrolling patients in January 2021. TRIAL REGISTRATION NUMBER: NCT04681534.

Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study.

Skin α-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of α-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of α-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The α-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher α-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The α-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, α-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.

Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions.

Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated.

Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy.

Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [123I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical work-up including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [123I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [123I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 ± 0.63 vs. 2.91 ± 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 ± 0.51 vs. 2.74 ± 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.

Directional Leads for Deep Brain Stimulation: Technical Notes and Experiences.

OBJECTIVE: Deep brain stimulation (DBS) is an approved treatment for movement disorders. Despite high precision in electrode placement, side effects do occur by current spread to adjacent fibers or nuclei. Directional leads (D-leads) are designed to adapt the volume of stimulation relative to the position within the target by horizontal and vertical current steering directions. The feasibility of implanting these new leads, possible difficulties, and complications were the focus of this study. MATERIAL AND METHODS: This analysis is based on 31 patients who underwent a DBS procedure with D-leads and an implantable pulse generator (IPG) capable of multiple independent current control and 31 patients who received non-D-leads with a similar IPG. While trajectory planning and most steps of the surgical procedure were identical to conventional DBS lead implantation, differences in indication, electrode handling, lead control, and complications were documented and analyzed in comparison to a control group with ring electrodes. RESULTS: During a consecutive series of 51 patients implanted with a DBS system, 31 patients (60.1%) were selected for implantation of D-leads and received 59 D-leads, 28 bilateral, and 3 unilateral implantations. The control group consisted of a consecutive series of a comparable time period, with 31 patients who received conventional ring electrodes. Indication of D-lead implantation was based on the anatomic conditions of the trajectory and target regions and the results of intraoperative test stimulations. In 1 patient, primary D-lead implantation on both sides was performed without any microelectrode implantation to minimize risk for hemorrhage. In the absence of an externally visible marker, the control of implant depth and of the orientation of the D-lead needs to be controlled by X-ray resulting in a longer fluoroscopy time and, therefore, higher X-ray dose compared to conventional lead implantations (415.53 vs. 328.96 Gy cm2; p = 0.09). Mean procedure duration for complete system implantation did not differ between either type of leads (ring electrodes vs. D-leads, 08:55 vs. 09:02 h:min). Surgical complications were unrelated to the type of electrode: surgical revision was necessary and successfully performed in 1 subcutaneous hematoma and 1 unilateral electrode dislocation. A rather rare complication, symptomatic idiopathic delayed-onset edema, was observed in 4 patients with D-leads. They recovered completely within 1-3 weeks, spontaneously or after short-term cortisone medication. In the control group, in a series of 31 patients (20 implanted with Medtronic 3389 lead and 11 with Boston Scientific Vercise lead), not a single problem of this kind was encountered at any time. CONCLUSION: Precise positioning of D-leads is more challenging than that of conventional DBS leads. By adding an external lead marker, control of optimal lead position and orientation is enhanced. In case of supposed increased risk for hemorrhage because of vessels crossing all possible trajectories in the pre-surgical navigated simulation program, primary D-lead implantation instead of the sharper microelectrodes may be a feasible alternative and it may offer more options than ring electrodes especially in these cases. Prospective studies comparing ring-mode stimulation to directional stimulation to examine the differences of the clinical effects have been started.

Mesencephalic Electrical Stimulation Reduces Neuroinflammation after Photothrombotic Stroke in Rats by Targeting the Cholinergic Anti-Inflammatory Pathway.

Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)+ CD4+-cells and α7nAchR+-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT+ CD4+-cells increased after MLR-HFS, whereas the amount of α7nAchR+-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia.

Genetically modified mouse models face limitations, especially when studying movement disorders, where most of the available transgenic rodent models do not present a motor phenotype resembling the clinical aspects of the human disease. Pharmacological mouse models allow for a more direct study of the pathomechanisms and their effect on the behavioral phenotype. Osmotic pumps connected to brain cannulas open up the possibility of creating pharmacological mouse models via local and chronic drug delivery. For the hereditary movement disorder of rapid-onset dystonia-parkinsonism, the loss-of-function mutation in the α3-subunit of the Na+/K+-ATPase can be simulated by a highly specific blockade via the glycoside ouabain. In order to locally block the α3-subunit in the basal ganglia and the cerebellum, which are the two brain structures believed to be heavily involved in the pathogenesis of rapid-onset dystonia-parkinsonism, a bilateral cannula is stereotaxically implanted into the striatum and an additional single cannula is introduced into the cerebellum. The cannulas are connected via vinyl tubing to two osmotic pumps, which are subcutaneously implanted on the back of the animals and allow for the chronic and precise delivery of ouabain. The pharmacological mouse model for rapid-onset dystonia-parkinsonism carries the additional advantage of recapitulating the clinical and pathological features of asymptomatic and symptomatic mutation carriers. Just like mutation carriers of rapid-onset dystonia parkinsonism, the ouabain-perfused mice develop dystonia-like movements only after additional exposure to stress. We demonstrate a mild stress paradigm and introduce two modified scoring systems for the assessment of a motor phenotype.

Deep Brain Stimulation in Movement Disorders: From Experimental Surgery to Evidence-Based Therapy.

Deep brain stimulation (DBS) of 3 different targets is the most important therapeutic innovation of the past 30 years for patients with fluctuating Parkinson's disease (PD), disabling dystonia, tremors, and refractory Gilles de la Tourette syndrome. When compared with medical treatment alone, controlled studies have shown better motor, nonmotor, and particularly quality-of-life outcomes with large effect sizes for advanced complicated PD that cannot be improved with medication, and also for PD patients with only early fluctuations. Class 1 studies have also shown superiority over medical treatment for generalized, segmental, and botulinum-toxin refractory focal cervical dystonia. Long-term efficacy is established for all indications with open studies. For tremors, open studies have shown that DBS is remarkably effective on PD and essential tremor, but efficacy on severe essential tremor and cerebellar tremors is limited by a tendency for tolerance/habituation, including concerns about long-term efficacy. Open studies of disabling Gilles de la Tourette syndrome show an improvement in tics. New developments hold a promise for further improvement. New hardware with directional stimulation and new stimulation paradigms are further areas of research. The targets of DBS are refined with new imaging processing that will help to diversify the surgical targets. New indications are being explored. Closed-loop DBS using brain or peripheral sensor signals have shown favorable clinical short-term results. Long-term data are lacking, and it is hoped that similar approaches for other movement or behavioral disorders may be developed. Exciting new developments carry the hope for a more pathophysiology-based approach for DBS for various brain circuit disorders. © 2019 International Parkinson and Movement Disorder Society.

Rescuing Suboptimal Outcomes of Subthalamic Deep Brain Stimulation in Parkinson Disease by Surgical Lead Revision.

BACKGROUND: Clinical trials have established subthalamic deep-brain-stimulation (STN-DBS) as a highly effective treatment for motor symptoms of Parkinson disease (PD), but in clinical practice outcomes are variable. Experienced centers are confronted with an increasing number of patients with partially "failed" STN-DBS, in whom motor benefit doesn't meet expectations. These patients require a complex multidisciplinary and standardized workup to identify the likely cause. OBJECTIVE: To describe outcomes in a series of PD patients undergoing lead revision for suboptimal motor benefit after STN-DBS surgery and characterize selection criteria for surgical revision. METHODS: We investigated 9 PD patients with STN-DBS, who had unsatisfactory outcomes despite intensive neurological management. Surgical revision was considered if the ratio of DBS vs levodopa-induced improvement of UPDRS-III (DBS-rr) was below 75% and the electrodes were found outside the dorsolateral STN. RESULTS: Fifteen electrodes were replaced via stereotactic revision surgery into the dorsolateral STN without any adverse effects. Median displacement distance was 4.1 mm (range 1.6-8.42 mm). Motor symptoms significantly improved (38.2 ± 6.6 to 15.5 ± 7.9 points, P < .001); DBS-rr increased from 64% to 190%. CONCLUSION: Patients with persistent OFFmotor symptoms after STN-DBS should be screened for levodopa-responsiveness, which can serve as a benchmark for best achievable motor benefit. Even small horizontal deviations of the lead from the optimal position within the dorsolateral STN can cause stimulation responses, which are markedly inferior to the levodopa response. Patients with an image confirmed lead displacement and preserved levodopa response are candidates for lead revision and can expect significant motor improvement from appropriate lead replacement.

Association of Pallidal Neurostimulation and Outcome Predictors With X-linked Dystonia Parkinsonism.

Importance: Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy. Objective: To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes. Design, Setting, and Participants: This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected. Exposures: All patients underwent bilateral GPi-DBS in Lübeck, Germany. Main Outcomes and Measures: Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes. Results: The study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004). Conclusions and Relevance: Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.

Pallidal neurostimulation versus botulinum toxin injections in the treatment of cervical dystonia: protocol of a randomized, sham-controlled trial (StimTox-CD).

BACKGROUND: Selective peripheral denervation via botulinum neurotoxin injections into dystonic muscles is the first-line treatment for cervical dystonia. Pallidal neurostimulation is a potent alternative, but currently restricted to patients failing on neurotoxin therapy. As botulinum neurotoxin is partially effective but often unsatisfactory in a relevant proportion of patients, earlier neurostimulation might be advantageous in providing stable symptom control and preventing disability. This trial intends to demonstrate, that pallidal neurostimulation is superior to neurotoxin injections in best clinical practice for controlling the symptoms of cervical dystonia and that it is safe in patients with a partial therapy response to peripheral denervation. We hypothesize a better outcome in everyday functioning and health-related quality of life of neurostimulated patients. METHODS: We aim to recruit 66 cervical dystonia patients into a double-blind comparison of pallidal neurostimulation versus botulinum neurotoxin type A. Eligible patients need ≥25% motor symptom reduction 4 weeks after a neurotoxin test injection, but are willing to undergo DBS surgery due to unsatisfactory symptom control. All participants will be implanted with a DBS system, and randomized into 2 groups: First group will receive effective neurostimulation and saline injections into dystonic muscles. Second group is treated with regular neurotoxin injections and undergoes a sham-stimulation. Primary outcome is the change in TWSTRS total score between baseline and 6 months of therapy. Secondary outcome parameters are corresponding changes in TWSTRS motor score, Tsui score, CDQ-24 and SF-36. Safety will be assessed by frequency and severity of reported adverse events. Statistical analysis includes intention-to-treat and per protocol populations, analysis based on imputation of missing values and analysis adjusting for differences in baseline TWSTRS. After 6 months of blinded treatment all patients will receive open-label neurostimulation and neurotoxin treatment as needed, and are followed up 48 weeks after randomization. PERSPECTIVE: We will assess if pallidal neurostimulation is a safe and effective alternative to selective peripheral denervation by botulinum toxin injections in cervical dystonia, which may be offered earlier in the course of disease based on patient preference. A positive study outcome would influence future treatment guidelines of cervical dystonia. TRIAL REGISTRATION: EudraCT registration number: 2016-001378-13.

Neurostimulation in tardive dystonia/dyskinesia: A delayed start, sham stimulation-controlled randomized trial.

INTRODUCTION: Growing evidence suggests that pallidal deep brain stimulation represents a potential new therapeutic avenue in tardive dystonia/dyskinesia, but controlled and blinded randomized studies (RCT) are missing. The present RCT compares dystonia/dyskinesia severity of pallidal neurostimulation in patients with tardive dystonia using a delayed-start design paradigm. METHODS: Dystonia/dyskinesia severity was assessed via blinded videos following pallidal neurostimulation at 3 (blinded phase) and 6 months (open extension phase). Primary endpoint was the percentage change of dystonia severity (Burke-Fahn-Marsden-Dystonia-Rating-Scale, BFMDRS) at 3 months between active vs. sham neurostimulation using blinded-video assessment. Secondary endpoints comprised clinical rating scores for movement disorders. Clinicaltrials.gov NCT00331669. RESULTS: Twenty-five patients were randomized (1:1) to active (n = 12) or sham neurostimulation (n = 13). In the intention-to-treat analyses the between group difference of dystonia severity (BFMDRS) between active vs. sham stimulation was not significant at 3 months. Three months post-randomisation dystonia severity improved significantly within the neurostimulation by 22.8% and non-significantly within the sham group (12.0%) compared to their respective baseline severity. During the open-label extension with both groups being actively treated, significant and pronounced improvements of 41.5% were observed via blinded evaluation. Adverse events (n = 10) occurred in 10/25 of patients during the 6 months, mostly related to surgical implantation of the device; all resolved without sequelae. CONCLUSION: The primary endpoint of this randomized trial was not significant, most likely due to incomplete recruitment. However, pronounced improvements of most secondary endpoints at 3 and 6 months provide evidence for efficacy and safety of pallidal neurostimulation in tardive dystonia.

Postoperative rehabilitation after deep brain stimulation surgery for movement disorders.

Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy for a set of neurological and psychiatric conditions and especially movement disorders such as Parkinson's disease, essential tremor and dystonia. Recent developments have improved the DBS technology. However, no unequivocal algorithms for an optimized postoperative care exist so far. The aim of this review is to provide a synopsis of the current clinical practice and to propose guidelines for postoperative and rehabilitative care of patients who undergo DBS. A standardized work-up in the DBS centers adapted to each patient's clinical state and needs is important, including a meticulous evaluation of clinical improvement and residual symptoms with a definition of goals for neurorehabilitation. Efficient and complete information transfer to subsequent caregivers is essential. A coordinated therapy within a multidisciplinary team (trained in movement disorders and DBS) is needed to achieve the long-range maximal efficiency. An optimized postoperative framework might ultimately lead to more effective results of DBS.